Neurofibromatosis is an inherited condition, which involves development of changes in the nervous system, skin, bones, and muscles manifested by the presence of multiple soft nodules, neurofibromas and associated with hyperpigmented spots. The disease is inherited as an autosomal dominant trait. German physician, Von Recklinghausen, is given the credit for clinical description of this condition (Von Recklinghausen, F., "Uber die multiplen fibrome der Haut und ihre Beziehung zu den multiplen, "Neuromen.", Hirschwald, Berlin (1882)). However, the evidence exists that the disease has been described earlier. The disease exists in two different forms: Type 1, known as Von Recklinghausen's disease, and Type 2. The gene for Type 1, NF1, has been located on chromosome 17 and for Type 2, NF2, on chromosome 22. It is estimated that one person in 4,000 inherits the trait for Type 1, and one person in 50,000 for Type 2.
Neurofibromatosis Type 1 is characterized by neurofibromas and cafe-au-lait spots. In addition, the patient may suffer from optic glioma, involvement of the bones and have Lisch nodules in the iris.
In neurofibromatosis Type 2, the patient has acoustic neuromas, meningiomas, and less frequently ependymomas and primitive neuroectodermal tumors located intracranially and intraspinally. A number of other neoplastic conditions occur in these patients, including neuroblastoma, Wilms' tumor, leukemia, pheochromocytoma, and thyroid carcinoma.
The disease is often not inherited in a straight-forward manner, but results from the factors that cause an imbalance in gene expression. This means that it may be transmitted by the nonmendelian process, such as genomic imprinting, whereby the expression or lack of expression of the gene is determined by the parental origin of the gene in a specific situation. Specifically, the differences in the material and paternal genes relate to the degree of methylation (Barlow, D. P., "Methylation and Imprinting: from Host Defense to Gene Regulation," Science 260:309-310 (1993); Ferguson-Smith, A. C., Reik, W., Surani, M. A., "Genomic Imprinting and Cancer," Cancer Surv. 9:487-503 (1990); and Reik, W.,"Genomic Imprinting and Genetic Disorders in Man," Trends Genet. 5:331-336 (1989)). The genes which are hypomethylated are transcriptionally active, whereas hypermethylated are inactive. This differs from the classical concept of inheritance, which assumes that alleles inherited from the paternal and maternal side are equally expressed.
The clinical features of the disorder are startlingly variable, even within the same family, indicating that other events must play a role in the eventual phenotype of the disease. The diagnostic criteria for NF1 include the presence of two or more of the following: (1) six or more cafe-au-lait macules more than 15 mm in greatest diameter in postpubertal individuals, or 5 mm in prepubertal individuals; (2) two or more neurofibromas of any type, or one plexiform neurofibroma; (3) freckling in the axillary or inguinal regions; (4) optic glioma; (5) two or more Lisch nodules (iris hamartomas); (6) a distinctive bony lesion such as sphenoid dysplasia or thinning of long-bone cortex, with or without pseudoarthrosis; (7) a first degree relative with NF1 (Von Recklinghausen, F., "Uber die multiplen fibrome der Haut und ihre Beziehung zu den multiplen, "Neuromen.," Hirschwald, Berlin (1882)). The penetrance of NF1 is extremely high if individuals are carefully examined, including the use of a slit-lamp to detect Lisch nodules. Under those circumstances, it is rare to identify an adult obligate gene carrier who does not meet the criteria listed above (Barlow, D. P., "Methylation and Imprinting: from Host Defense to Gene Regulation," Science 260:309-310 (1993)).
The diagnosis of neurofibromatosis Type 2 can be established when one of the following is present: (1) bilateral 8th cranial nerve masses, (2) first degree relative with neurofibromatosis Type 2, and either unilateral 8th nerve mass or any one of the following: neurofibroma, meningioma, glioma, schwannoma, posterior capsular cataract or opacity at a young age (Neurofibromatosis: National Institutes of Health: Consensus Development Conference Statement 6:1 (1987)).
Current methods of treatment of neurofibromatosis focus on alleviation of the symptoms. Skin lesions are removed through cosmetic surgery. Intracranial and intraspinal nodules are treated by surgery, irradiation, or chemotherapy.
The nodules located in the central nervous system can cause neurological deficit. Depending on the nodule location, the patient may have facial nerve paralysis, decreased hearing or deafness, decreased visual acuity or visual field defects, the symptoms of increased intracranial pressure, paralysis, and diencephalic syndrome. The involvement of the superior eyelid and the eyeball can cause congenital glaucoma, the changes in the bone can result in scoliosis, kyphosis, pseudoarthrosis and bowing of the tibia. Approximately 40% of patients have learning disabilities and 10% mental retardation. The patient who has significant neurological symptoms can be helped by surgical resection of the nodule. Radiation therapy and cytotoxic chemotherapy have been applied in the attempts to reduce the size of the nodules.
Without wishing to bound to any proposed theory, the present inventor postulates that the human body possesses a Biochemical Defense System (BDS) (Burzynski, S. R., Internat. J. Exp. Clin. Chemother. 2:63 (1989) and Burzynski, S. R., 17th Internat. Cong. Chemother., Berlin (1991)). This system parallels the immune defense, but protects the organism against the enemy within the body. The main purpose is no longer the defense against the micro-organism, but defense against defective cells. Chemical components of this biochemical defense system are peptides, amino acid derivatives and organic acids defined as antineoplastons (Burzynski, S. R., Physiol. Chem. Phys. 8:275 (1976) and Burzynski, S. R., U.S. Pat. No. 4,470,970). The mechanism of defense is based not on destruction, but on the reprogramming of defective cells through induction of differentiation.
Antineoplastons discovered by the inventor are small molecular peptides, amino acid derivatives, and certain organic acids, which protect the organism against the development of cancer by a nonimmune mechanism (Burzynski, S. R., "Antineoplastons: Biochemical Defense Against Cancer," Physiol. Chem. Phys. 8:275-279 (1976) and Burzynski, S. R., "Novel Differentiation Inducers," Recent Advances in Chemotherapy, Adam, D. (Ed.), Futuramed Publishers, Munich, Germany (1992)).
The research on antineoplastons began in Poland in 1967 (Burzynski, S. R., Experientia 25:490 (1969) and Burzynski, S. R., Drugs Exptl. Clin. Res. Suppl. 1 12:1 (1986)). Initially, the work concentrated on the isolation of peptides which exist in the blood of healthy people and are deficient in cancer patients. Due to the small amount of raw material available for the study, in the following years, antineoplastons were isolated from urine instead of blood. In 1980, the structure of the first antineoplaston was identified and reproduced synthetically (Burzynski, S. R. et at., Proc. 13th Internat. Cong. Chemother., Vienna, Austria 17, P.S. 12. 4. 11-4(1983)).
Antineoplastons are divided into two groups. One group contains compounds which have a wide spectrum of activity and includes Antineoplaston A1, A2, A3, A4, A5, A10, AS2-1 and AS2-5. Antineoplastons A1, A2, A3, A4 and A5 contain peptides isolated from urine, and Antineoplaston A10, AS2-1 and AS2-5 are synthetic products. See, e.g., U.S. Pat. Nos. 4,470,970, 4,558,057 and 4,559,325. In addition to the first group, there are antineoplastons that are active against a single specific type of neoplasm, such as Antineoplaston H, L and 0. Antineoplaston A10 is the first active ingredient isolated and reproduced by synthesis. Acid hydrolysis of Antineoplaston A10 initially produces phenylacetylglutamine and phenylacetylisoglutamine. When hydrolysis is carried further, the products of reaction include phenylacetic acid, glutamic acid and ammonia. The sodium salt of phenylacetylglutamine was named Antineoplaston AS2-5 and the mixture of the sodium salts of phenylacetyl/glutamine and phenylacetic acid in the ratio of 1:4 was named Antineoplaston AS2-1 (Burzynski, S. R. et at., Drugs Exptl. Clin. Res. Suppl. 1 12:11 (1986)).
The mechanism of action of Antineoplaston A2, A3, A5 and AS2-1 involves inhibition of methylation of DNA. The methylation of DNA is a complex, enzymatic reaction which requires three enzymes: methyltransferase, methionine adenos yltransferase, and S-adenosylhomocysteine hydrolase. Numerous published data confirm that antineoplastons are effective hypomethylating agents (Liau, M. C., Burzynski, S. R., "Altered Methylation Complex Isoenzymes as Selective Targets for Cancer Chemotherapy," Drugs Exptl. Clin. Res. 12 (Suppl. 1):77-86 (1986); Liau, M. C., Lee, S. S., Burzynski, S. R., "Modulation of Cancer Methylation Complex Isozymes as a Decisive Factor in the Induction of Terminal Differentiation Mediated by Antineoplaston A5,"Internat. J. Tissue Reactions 12 (Suppl.):27-36 (1990); Lee, S. S., Burzynski, S. R., "Induction of Differentiation of HL-60 Human Promyelocytic Leukemic Cell by Antineoplaston A5," Internat. J. Tissue Reactions 12 (Suppl.):37-42 (1990); Liau, M. C., Lee, S. S., Burzynski, S. R., "Differentiation Inducing Components of Antineoplaston A5," Adv. Exptl. Clin. Chemother. 6:9-25 (1988); Liau, M. C., Lee, S. S., Burzynski, S. R., "Hypomethylation of Nucleic Acids: A Key to the Induction of Terminal Differentiation," Internat. J. Exptl. Clin. Chemother. 2:187-199 (1989); Lee, S. S., Burzynski, S. R., "Inducibility of HL-60 Leukemic Cells to Undergo Terminal Differentiation After Repeated Treatment with Antineoplaston A5, " Internat. J. Exptl. Clin. Chemother. 3:125-128 (1990); Lee, S. S., Burzynski, S. R., "Antineoplaston A5: A Growth Inhibitor for Cancerous Cells and Growth Stimulator for Normal Cells," Internat. J. Exptl. Clin. Chemother. 4:63-65 (1991); Liau, M. C., Luong, Y., Liau, C. P., Burzynski, S. R., "Prevention of Drug-Induced DNA Hypermethylation by Antineoplastons," Recent Advances in Chemotherapy, Adam, D. (Ed.), Futuramed Publishers, Munich, Germany (1992); and Liau, M. C., Liau, C. P., Burzynski, S. R., "Potentiation of Induced Terminal Differentiation by Phenylacetic Acid and Related Chemicals," Internat. J. Exptl. Clin. Chemother. 5:9-17 (1992)).
In the case where the inherited disorder, such as NF1 or NF2, is due to inactivity of the gene, which is hypermethylated, decreasing methylation of such gene can result in expression of the gene, and theoretically in alleviation of the signs and symptoms of the disease.